CNS Pharmacology for Dentistry PDF

1  CNS PHARMACOLOGY Jo-Ann S. Belotindos, MPP, MPH, RPh School of Health & Allied Health Sciences College of Pharmacy, SWU PHINMA 2  GENERAL ANESTHETICS LOCAL ANESTHETICS SEDATIVE-HYPNOTICS ANTI PARKINSONISM ANTI PSYCHOTICS...

1  CNS PHARMACOLOGY Jo-Ann S. Belotindos, MPP, MPH, RPh School of Health & Allied Health Sciences College of Pharmacy, SWU PHINMA 2  GENERAL ANESTHETICS LOCAL ANESTHETICS SEDATIVE-HYPNOTICS ANTI PARKINSONISM ANTI PSYCHOTICS & LITHIUM ANTI DEPRESSANT ANTI SEIZURE ALCOHOL 3 SEDATIVE-HYPNOTIC DRUGS 4  SEDATIVE = anxiolytic = agent that reduce anxiety and exert a calming effect. HYPNOTIC = an agent that produce drowsiness and encourage the onset and maintenance of a state of sleep. = involve more pronounce depression of the CNS (achieved by increasing the dose) 5  GRADED dose-dependent depression of the CNS function is a characteristic of most sedative-hypnotics! individual drugs differ in the relationship between the dose and the degree of CNS depression. Example include older sedative-hypnotics – barbiturates and alcohols. With such drugs, an increase in dose higher than that needed for hypnosis may lead to a state of general anesthesia. At still higher doses, these sedative-hypnotics may depress respiratory and vasomotor centers in the medulla – leading to coma and death. 6  SEDATIVE-HYPNOTIC DRUGS BENZODIAZEPINES - Clorazepate - Alprazolam - Chlordiazepoxide - Clonazepam - Diazepam - Estazolam - Flurazepam - Lorazepam - Midazolam - Oxazepam - Quazepam - Temazepam - Triazolam - Nitrazepam 7  BARBITURATES - Amobarbital - Butabarbital - Pentobarbital - Secobarbital ( short to intermediate acting ) - Mephobarbital - Phenobarbital ( long – acting ) - Thiopental ( ultra – short acting ) BENZODIAZEPINE ANTAGONIST - Flumazenil 8  NEWER HYPNOTICS - Eszopiclone - Zaleplon - Zolpidem MELATONIN RECEPTOR AGONIST - Ramelteon - Tasimelteon OREXIN ANTAGONIST - Suvorexant - Almorexant 5-HT-RECEPTOR AGONIST - Buspirone 9  Glutethimide and meprobamate ▪ are equivalent to barbiturates in their pharmacologic effects ▪ They are rarely used. Ethanol and chloral hydrate Antipsychotics Antidepressants – currently used widely in chronic anxiety d/o Hydroxyzine -- Antihistamines -- exert marked effects on the Promethazine peripheral NS 10  The benzodiazepines are widely used sedative-hypnotics. Structures are in a 1,4-benzodiazepines, and most contain a carboxamide group in the 7-membered heterocyclic ring structure. A substituent in the 7 position, such as a halogen or a nitro group, is required for sedative-hypnotic activity. The structures of triazolam and alprazolam include the addition of a triazole ring at the1,2-position. 11  SEDATIVE-HYPNOTICS PHARMACOKINETICS: - lipid solubility plays a major role in determining the rate at which a particular sedative-hypnotic enters the CNS. (this property is responsible for the rapid onset of CNS effects of Triazolam, Thiopental, newer hypnotics) - most of the barbiturates and other sedative-hypnotics as well as the newer hypnotics ( eszopiclone, zaleplon, zolpidem) are absorbed rapidly into the blood following oral administration. 12 - All sedative-hypnotics cross the placental barrier during pregnancy. - If given during the predelivery period, they may contribute to the depression of neonatal vital functions. - Are also detectable in breast milk and may exert depressant effects in the nursing infant. 13  BIOTRANSFORMATION: - metabolic transformation to more water-soluble metabolites is necessary for clearance of sedative-hypnotics from the body through the microsomal drug-metabolizing enzyme systems. Elimination half-life of these drugs depends mainly on the rate of their metabolic transformation. 1. BENZODIAZEPINES - Hepatic metabolism accounts for the clearance of all benzodiazepines. - Most undergo microsomal oxidation (phase I reaction), including N dealkylation, and aliphatic hydroxylation catalyzed by CYP 450 especially CYP3A4. 14 - The metabolites are subsequently conjugated (phase II reaction) to form glucuronides that are excreted in the urine. - Many phase I metabolites of benzodiazepines are pharmacologically active, some with long half – lives. - Example, desmethyldiazepam, which has an elimination half-life of more than 40 hours, is an active metabolite of chlordiazepoxide, diazepam, prazepam, and clorazepate. 15 -Alprazolam and triazolam undergo α-hydroxylation, and the metabolites appear to exert short-lived pharmacologic effects because they are rapidly conjugated to form inactive glucuronides. -The short elimination half-life of triazolam (2–3 hours) favors its use as a hypnotic rather than as a sedative drug. 16  Benzodiazepines for which the parent drug or active metabolites have long half – lives are more likely to cause cumulative effects (ex. excessive drowsiness) with multiple doses. Cumulative and residual effects such as excessive drowsiness appear to be less of a problem with drugs as estazolam, oxazepam, and lorazepam, which have relatively short half-lives and are metabolized directly to inactive glucuronides. The metabolism of several commonly used BZ including diazepam, midazolam, and triazolam is affected by inhibitors and inducers of hepatic P450 isozymes 17  Chlordiazepoxide Diazepam Prazepam Clorazepate (inactive) Desmethylchlordiazepoxide * Alprazolam & Demoxepam* Desmethyldiazepam* Triazolam Alpha-hydroxy Oxazepam* metabolites* Hydroxyethyl flurazepam* CONJUGATI Lorazepam Flurazepam Desalkyl-fluraz ON epam* URINARY EXCRETION 18 2. BARBITURATES - With the exception of phenobarbital, only insignificant quantities of the barbiturates are excreted unchanged. - The major metabolic pathways involve oxidation by hepatic enzymes to form alcohols, acids, and ketones which appear in the urine as glucuronide conjugates. - Elimination half-lives of secobarbital and pentobarbital range from 18 to 48 hours in different individuals. 19 - The elimination half-life of phenobarbital in humans is 4-5 days. - Multiple dosing with these agents can lead to cumulative effects. 3. NEWER HYPNOTICS Zolpidem - an imidazopyridine - is rapidly metabolized to inactive metabolites via oxidation and hydroxylation by hepatic cytochrome P450 including the CYP3A4 isozyme. 20  Zaleplon - is a pyrazolopyrimidine - is metabolized to inactive metabolites mainly by hepatic aldehyde oxidase and partly by the cytochrome P450 isoform CYP3A4. - Dosage should be reduced in patients with hepatic impairment and in the elderly. - Cimetidine, which inhibits both aldehyde dehydrogenase and CYP3A4, markedly increases the peak plasma level of zaleplon 21  Eszopiclone - is a cyclopyrrolone. - is an (S) enantiomer of zopiclone, a hypnotic drug. - metabolized by hepatic cytochromes P450 (especially CYP3A4) to form the inactive N-oxide derivative and weakly active desmethyleszopiclone. - The elimination half-life of eszopiclone is prolonged in the elderly and in the presence of inhibitors of CYP3A4 (eg, ketoconazole). Inducers of CYP3A4 (eg, rifampin) increase the hepatic metabolism of eszopiclone. 22  RAMELTEON/TASIMELTEON Is an agonist at MT1 and MT2 melatonin receptors located in the suprachiasmatic nuclei of the brain. A novel hypnotic drug prescribed specifically for patients who have difficulty in falling asleep. It reduces the latency of persistent sleep with no effects on sleep architecture and no rebound insomnia or significant withdrawal symptoms. rapidly absorbed after oral administration and undergoes extensive first-pass metabolism, forming an active metabolite with longer half-life (2–5 hours) than the parent drug.  CYP1A2 is mainly responsible for the metabolism of ramelteon, but the CYP2C9 isoform is also involved. The drug should not be used in combination with inhibitors of CYP1A2 (eg, ciprofloxacin, fluvoxamine, tacrine, zileuton) or CYP2C9 (eg, fluconazole) and should be used with caution in patients with liver dysfunction. CYP inducer rifampin reduces the plasma levels of both ramelteon and its active metabolite. Adverse effects include dizziness, somnolence, fatigue, and endocrine changes; decreases in testosterone and increases in prolactin. 24  Concurrent use with the antidepressant fluvoxamine increases the peak plasma concentration of ramelteon over 50-fold! Tasimelteon is similar and is approved for non-24 hour sleep-wake disorder. These drugs have no direct effects on GABAergic neurotransmission in the central nervous system. 25  BUSPIRONE Has selective anxiolytic effects. It relieves anxiety without causing marked sedative, hypnotic, or euphoric effects. It has no anticonvulsant or muscle relaxant properties. Buspirone does not interact directly with GABAergic systems. It may exert its anxiolytic effects by acting as a partial agonist at brain 5-HT1A receptors, but it also has affinity for brain dopamine D2 receptors. Buspirone treated patients show no rebound anxiety or withdrawal signs on abrupt discontinuance. 26  the anxiolytic effects may take 3-4 weeks to become established, making the drug unsuitable for management of acute anxiety states. It is used in generalized anxiety states but is less effective in panic disorders. Rapidly absorbed orally but undergoes extensive first-pass metabolism via hydroxylation and dealkylation reactions to form several active metabolites. The major metabolite is 1-(2-pyrimidyl)-piperazine (1-PP), which has α2-adrenoceptor-blocking actions. Elimination half-life is 2 – 4H. Inhibitors of CYP3A4 (eg, erythromycin, ketoconazole, grapefruit juice, nefazodone) can markedly increase its plasma levels. 27  Buspirone causes less psychomotor impairment and does not affect driving skills. ADRs: nonspecific chest pain, tachycardia, palpitations, dizziness, nervousness, tinnitus, gastrointestinal distress, and paresthesias and a dose-dependent pupillary constriction may occur. Blood pressure may be significantly elevated in patients receiving MAO inhibitors. Buspirone is an FDA category B drug in terms of its use in pregnancy. 28  EXCRETION: - the water soluble metabolites of sedative-hypnotics, mostly formed via the conjugation of phase I metabolites, are excreted mainly via the kidney. - Phenobarbital is excreted unchanged in the urine to a certain extent (20-30% in humans), and its elimination rate can be increased by alkalinization of the urine. ( This is partly due to increased ionization at alkaline pH since phenobarbital is a weak acid). 29 ORGAN LEVEL EFFECTS SEDATION = BZ, barbiturates, and most older sedative-hypnotic drugs exert calming effects with concomitant reduction of anxiety at relatively low doses. = the anxiolytic actions of sedative-hypnotics are accompanied by some depressant effects on psychomotor and cognitive functions. = the BZ also exert dose-dependent anterograde 31 amnesic effects.  HYPNOSIS = all of the sedative-hypnotics induce sleep if high enough doses are given. = the effects on the stages of sleep depend on several factors, including: the specific drug, the dose, and the frequency of its administration. 32  ANESTHESIA = high doses of certain sedative-hypnotics depress the CNS to the point known as stage III of general anesthesia. * among the Barbiturates, THIOPENTAL & METHOHEXITAL are very lipid-soluble, penetrating brain tissue rapidly following IV administration. * Among BZ, DIAZEPAM, LORAZEPAM, MIDAZOLAM are used intravenously in anesthesia often in combination with other agents. 33  ANTICONVULSANT EFFECTS = are capable of inhibiting the development and spread of epileptiform electrical activity in the CNS. = several BZ including – CLONAZEPAM, NITRAZEPAM, LORAZEPAM, DIAZEPAM are selective clinically useful in the management of seizures. = of the barbiturates – PHENOBARBITAL, METHARBITAL are effective in the treatment of generalized tonic-clonic seizures. 34  MUSCLE RELAXATION = some like the carbamates ( Meprobamate) exert inhibitory effects on polysynaptic reflexes and internuncial transmission and at high doses may also depress transmission at the skeletal neuromuscular junction. 35  EFFECTS ON RESPIRATION & CARDIOVASCULAR FUNCTION = at hypnotic doses in healthy patients, the effects are comparable to changes during natural sleep. = however, even at therapeutic doses, sedative-hypnotics can produce significant respiratory depression in patient with pulmonary disease. = depression of the medullary respiratory center is the usual cause of death due to overdose. 36 = at doses of causing hypnosis, no significant effects on the CVS observed among healthy patients. = in hypovolemic states, heart failure, and other CV diseases, normal doses of sedative-hypnotics may cause cardiovascular depression. 37 = at toxic doses, myocardial contractility and vascular tone may both be depressed by central and peripheral effects leading to circulatory collapse. = Respiratory and cardiovascular effects are more marked when sedative-hypnotics are given intravenously. 38  TOLERANCE = decreased responsiveness to a drug following repeated exposure. = common feature of sedative-hypnotic use. It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep. Partial cross-tolerance occurs between the sedative-hypnotics and also with ethanol. 39  PHYSIOLOGIC DEPENDENCE = an altered physiologic state that requires continuous drug administration to prevent an abstinence or withdrawal syndrome. = characterized by increased anxiety, insomnia, CNS excitability that may progress to convulsions. 40 ▪ Most sedative-hypnotics – including BZ are capable of causing physiologic dependence when used on a long-term basis. The abrupt cessation of Zolpidem, Zaleplon, Eszopiclone may also result in withdrawal symptoms, though of less intensity than with BZ. 41  CLINICAL USES OF SEDATIVE-HYPNOTICS: For relief of anxiety As a component of balanced anesthesia (IV administration) Insomnia For control of ethanol or other Sedation and amnesia before and sedative-hypnotic withdrawal during medical and surgical states procedures Treatment of epilepsy and seizure For muscle relaxation in specific states neuromuscular disorders As diagnostic aids or for treatment in psychiatry 42  CLINICAL TOXICOLOGY: ADVERSE EFFECTS OF BARBITURATES: The most common side effects of Barbiturates are light-headedness, dizziness, drowsiness, and unsteadiness or clumsiness. Depression, confusion, or unusual excitement, bleeding sores on the lips, chest pain or tightness in the chest, fever, muscle or joint pain, skin problems, such as rash, hives, or red, thickened, or scaly skin, sore throat, sores or painful white spots in the mouth, swollen eyelids, face, or lips and wheezing. 43  Because barbiturates enhance porphyrin synthesis, they are absolutely contraindicated in patients with a history of acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, or symptomatic porphyria. 44 ADVERSE EFFECTS of BENZODIAZEPINES: - Sedation - ataxia - anterograde amnesia - light-headedness - Paradoxic excitement in children. - Menstrual irregularities 45  FLUMAZENIL Act as a competitive BZ antagonist It blocks many of the actions of BZ, Zolpidem, Zaleplon, and Eszopiclone but does not antagonize the CNS effects of other sedative-hypnotics, ethanol, opioids, or general anesthetics. 46  Flumazenil is approved for use in reversing the CNS depressant effects of BZ overdose and to hasten recovery following use of these drugs in anesthetic and diagnostic procedures. When given intravenously, flumazenil acts rapidly but has a short half-life (0.7–1.3 hours) due to rapid hepatic clearance. Adverse effects: agitation, confusion, dizziness, nausea 47  FDA assignment of individual benzodiazepines to either category D or X in terms of pregnancy risk: Most barbiturates are FDA pregnancy category D. Eszopiclone, ramelteon, zaleplon, and zolpidem are category C Buspirone is a category B drug 48  DRUG INTERACTIONS: most common drug interactions involving sedative-hypnotics are interactions with other CNS depressant drugs, leading to additive effects. These interactions have some therapeutic usefulness when these drugs are used as adjuvants in anesthesia practice. such interactions can lead to serious consequences, including enhanced depression with concomitant use of many other drugs. 49  Additive effects can be predicted with concomitant use of alcoholic beverages, opioid analgesics, anticonvulsants, and phenothiazines. Less obvious but just as important is enhanced CNS depression with a variety of antihistamines, antihypertensive agents, and TCA antidepressants. 50 51 GENERAL ANESTHETICS 52  ANALGESIA = a state of decreased awareness of pain, sometimes with amnesia. GENERAL ANESTHESIA = is a state characterized by unconsciousness, analgesia, amnesia, skeletal muscle relaxation and loss of reflexes. 53 54 55  TYPES OF GENERAL ANESTHESIA INTRAVENOUS ANESTHETICS a. BARBITURATES ( Thiopental, Methohexital ) b. BENZODIAZEPINES ( Midazolam, Diazepam ) c. PROPOFOL d. KETAMINE 56 e. OPIOID ANALGESICS ( Morphine, Fentanyl, Sufentanil, Alfentanil, Remifentanil ) f. MISCELLANEOUS SEDATIVE-HYPNOTICS ( Etomidate, Dexmedetomidine, Droperidol ) 57  INHALATION ANESTHETICS - VOLATILE LIQUIDS ( Halothane, Enflurane, Methoxyflurane, Isoflurane, Desflurane, Sevoflurane ) - GAS ( Nitrous oxide ) 58  MECHANISM OF ACTION inhibit the presynaptic voltage-gated sodium channels in glutamatergic synapse, which inhibits the excitation of the neuron by blocking the release of presynaptic neurotransmitters 59  One of the most important factors influencing the transfer of an anesthetic from the lungs to the arterial blood is its SOLUBILITY characteristics. The blood:gas partition coefficient is a useful index of solubility and defines the relative affinity of an anesthetic for the blood compared with that of inspired gas. The partition coefficients for desflurane and nitrous oxide, which are relatively insoluble in blood, are extremely low. 60 61  All inhaled anesthetics tend to increase right atrial pressure in a dose-related fashion, which reflects depression of myocardial function. Enflurane and halothane have greater myocardial depressant effects than isoflurane and the newer, less soluble halogenated anesthetics. Nitrous oxide found to depress the myocardium in a concentration-dependent manner. (administration of nitrous oxide in combination with the more potent inhaled (volatile) anesthetics can minimize cardiac depressant effects owing to its anesthetic-sparing effect) Sevoflurane and desflurane are less likely to produce arrhythmias. 62 63  All volatile anesthetics are respiratory depressants. Isoflurane and enflurane being the most depressant. All volatile anesthetics increase the resting level of PaCO2 (the partial pressure of carbon dioxide in arterial blood). The respiratory depressant effects of anesthetics are overcome by assisting (or controlling) ventilation mechanically. 64 65  On the KIDNEY depending on the concentration, volatile anesthetics decrease the glomerular filtration rate and renal blood flow and increase the filtration fraction. 66  EFFECTS ON UTERINE SMOOTH MUSCLE Nitrous oxide have little effect on uterine musculature. The halogenated anesthetics are potent uterine muscle relaxants. This pharmacologic effect can be used to advantage when profound uterine relaxation is required for an intrauterine fetal manipulation or manual extraction of a retained placenta during delivery. However, it can also lead to increased uterine bleeding. 67  TOXICITY Hepatotoxicity ( Halothane ) Nephrotoxicity Malignant hyperthermia 68  EFFECTS ON REPRODUCTIVE ORGANS - higher incidence of miscarriages, abortions HEMATOTOXICITY - prolonged exposure to nitrous oxide decreases methionine synthase activity and theoretically can cause megaloblastic anemia. 69  IV ANESTHETICS Intravenous agents are commonly used for induction of general anesthesia. Most IV anesthetics lack antinociceptive (analgesic) properties Their potency is adequate for short superficial surgical procedures when combined with nitrous oxide or local anesthetics, or both. Adjunctive use of potent opioids (eg, fentanyl, sufentanil or remifentanil) contributes to improved CV stability, enhanced sedation, and perioperative analgesia. 70  BARBITURATES Thiopental is a barbiturate commonly used for induction of anesthesia. After an IV bolus injection, thiopental rapidly crosses the B-B-B and, if given in sufficient dosage, produces loss of consciousness in one circulation time. Thiopental rapidly diffuses out of the brain and other highly vascular tissues and is redistributed to muscle and fat.  BENZODIAZEPINES Diazepam, lorazepam, and midazolam are used for preanesthetic medication and as adjuvants during surgical procedures performed under local anesthesia. As a result of their sedative, anxiolytic, and amnestic properties, and their ability to control acute agitation, these compounds are considered to be the drugs of choice for premedication. Diazepam and lorazepam are not water-soluble, and their intravenous use necessitates nonaqueous vehicles, which cause pain and local irritation. Midazolam is water-soluble and is the benzodiazepine of choice for parenteral administration. 72  OPIOID ANALGESICS Remifentanil, a potent and extremely short-acting opioid has been used to minimize residual ventilatory depression. Lower doses of Fentanyl and Sufentanil have been used as premedication and as an adjunct to both intravenous and inhaled anesthetics to provide perioperative analgesia. 73  Fentanyl and Droperidol administered together produce analgesia and amnesia and combined with nitrous oxide provide a state referred to as neuroleptanesthesia 74  PROPOFOL 2,6-DIISOPROPYLPHENOL Has become the most popular IV anesthetic Is used for both induction and maintenance of anesthesia as part of total IV or balanced anesthesia techniques. Agent of choice for ambulatory surgery. (out-patient surgery) 75  ETOMIDATE A carboxylated imidazole. For induction of anesthesia in patients with limited cardiovascular reserve. Its major advantage is that it causes minimal cardiovascular and respiratory depression. 76  KETAMINE It produces a dissociative anesthetic state characterized by catatonia, amnesia, analgesia, with or without loss of consciousness (hypnosis) The only IV anesthetic that possesses both analgesic properties and the ability to produce dose-related CV stimulation. 77 LOCAL ANESTHETICS 78 LOCAL ANESTHESIA = is the condition that results when sensory transmission from a local area of the body to the CNS is blocked. = can be administered locally by topical application or by injection in the target area, the anesthetic effect can be restricted to a localized area. = when given IV, these drugs have effects on other tissues. 79  LOCAL ANESTHETICS ESTERS AMIDES LONG SHORT SURFACE LONG MEDIUM ACTION ACTION ACTION ACTION ACTION Bupivacaine Tetracaine Ropivacaine Levobupivacaine Benzocaine Lidocaine Procaine Mepivacaine Cocaine Prilocaine (medium) Articaine Benzocaine (surface use only) 80  / Levobupivacaine Lidocaine 81  Local anesthetics are less effective when they are injected into infected (acidic) tissues because a smaller percentage of the local anesthetic is nonionized and available for diffusion across the membrane in an environment with a low extracellular pH. Systemic absorption of injected local anesthetic from the site of administration is determined by several factors: dosage, site of injection, drug-tissue binding, local tissue blood flow, use of vasoconstrictors (eg, epinephrine), and the physicochemical properties of the drug itself. 82  Vasoconstrictor substances such as epinephrine reduce systemic absorption of local anesthetics from the injection site by decreasing blood flow in these areas. This is important for drugs with intermediate or short durations of action such as procaine, lidocaine, and mepivacaine (but not prilocaine). 83  The amide local anesthetics are widely distributed after IV bolus administration. Sequestration can occur in lipophilic storage sites (eg, fat). After an initial rapid distribution phase, which consists of uptake into highly perfused organs such as the brain, liver, kidney, and heart, a slower distribution phase occurs with uptake into moderately well-perfused tissues, such as muscle and the GIT. 84 METABOLISM AND EXCRETION The local anesthetics are converted in the liver (amide type) or in plasma (ester type) to more water-soluble metabolites, which are excreted in the urine. Acidification of urine promotes ionization of the tertiary amine base to the more water-soluble charged form, leading to more rapid elimination. Ester-type local anesthetics are hydrolyzed very rapidly in the blood by circulating butyrylcholinesterase (pseudocholinesterase) to inactive metabolites. 85  MECHANISM OF ACTION Block voltage-dependent sodium channels and reduce the influx of sodium ions, thereby preventing depolarization of the membrane and blocking conduction of the action potential. 86 87 COCAINE The first local anesthetic introduced into medical practice. Isolated by Niemann in 1860 and introduced into practice by Koller in 1884 as a topical ophthalmic anesthetic. Despite the fact that its chronic use was associated with psychological dependence (addiction), cocaine was used clinically because it was the only local anesthetic drug available for 30 years. Cocaine has intrinsic sympathomimetic action due to its inhibition of NE reuptake into nerve terminals and possesses high surface (topical) activity. 88  Repeated injections of LA can result in loss of effectiveness (i.e, tachyphylaxis) due to extracellular acidosis. 89  TOXICITY CNS - sleepiness - light-headedness or sedation - visual and auditory disturbances - circumoral & tongue numbness - metallic taste - restlessness - nystagmus & muscular twitching - tonic-clonic convulsions 90  CVS - local anesthetics block cardiac sodium channels and thus depress abnormal cardiac pacemaker activity, excitability, and conduction. - all LA are vasodilators except cocaine, patients with preexisting CV disease may develop heart block. - BUPIVACAINE may produce severe CV toxicity, including arrhythmias and hypotension, if given intravenously. 91 ** COCAINE`s cardiovascular toxicity includes severe hypertension with cerebral hemorrhage, cardiac arrhythmias and MI. PRILOCAINE is metabolized to products that include an agent capable of causing methemoglobinemia (patient may appear cyanotic and the blood ʺchocolate-coloredʺ Allergic reactions specially with ester-type of LA 92 93